Systems and Methods for Hematocrit Impedance Measurement Using Switched Capacitor Accumulator

ABSTRACT

There is provided a system for measuring a property of a sample that comprises a test strip for collecting the sample; a diagnostic measuring device configured to receive the test strip and measure a concentration of an analyte in the sample received on the test strip; and the diagnostic measuring device further comprising a processor programmed to execute an analyte correction for correcting a measurement of the sample due to one or more interferents, comprising: calculating an interferent impedance measurement including a magnitude measurement and a phase measurement using a switched capacitor accumulator to measure a phase angle; and adjusting the measurement of the analyte in the sample using that the calculated interferent impedance measurement.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalApplication No. 62/803,732, filed Feb. 11, 2019, the entirety of whichis hereby incorporated herein by reference.

FIELD

The present disclosure relates to systems and methods for hematocritimpedance measurement in connection with blood glucose and hemoglobinmeters.

BACKGROUND

Many industries have a commercial need to monitor the concentration ofparticular constituents in a fluid. In the health care field, forexample, individuals with diabetes have a need to monitor a particularconstituent within their bodily fluids. A number of systems areavailable that allow people to test a body fluid, such as, blood, urine,or saliva, to conveniently monitor the level of a particular fluidconstituent, such as, cholesterol, proteins, and glucose. Such systemstypically include a test strip where the user applies a fluid sample anda meter that “reads” the test strip to determine the level of the testedconstituent in the fluid sample. A Blood Glucose Monitor (BGM) is anexample of such a device. A hemoglobin meter (HbM) is another.

Conventionally, a BGM is a portable handheld device used to measureblood glucose levels for users with Type I or Type II diabetes.Typically, the user purchases small strips (approximately 20-30 mm×5-9mm) that interface with the BGM or HbM. The user draws a tiny amount ofblood (a few microliters) from a finger or other area using a lancer,applies a blood droplet sample onto the exposed end of the strip, andthen inserts the connector end of the strip into the BGM connector port.A chemical reaction occurs between the blood sample and the chemistry onthe strip, which is measured by the BGM to determine the blood glucoselevel in units of mg/dL or mmol/L, or Kg/L depending on regionalpreferences. Units for hemobolgin (Hb) are in g/dL

Two resources that are constrained in handheld blood glucose meter (BGM)and hemoglobin meter (HbM) designs are energy and processing power. Tokeep the cost and size down, portable BGMs are typically powered by asmall single CR2032 type coin cell Lithium battery or similar. The peaksource current of this type of battery is very low and the total currentcapacity is also very low, from tens to a few hundred milli-Amp-hours(mAh). Yet, this small battery is expected to last the life of themeter, or at least require extremely infrequent battery changes. A deadbattery would present an opportunity for the customer to purchase acompetitor's brand meter and thereby purchase the competitors stripsgoing forward.

SUMMARY

The present disclosure relates to systems and methods for hematocritimpedance measurement in connection with blood glucose and hemoglobinmeters.

In some aspects, the present disclosure provides a system for measuringa property of a sample that comprises a test strip for collecting thesample; a diagnostic measuring device configured to receive the teststrip and measure a concentration of an analyte in the sample receivedon the test strip; and the diagnostic measuring device furthercomprising a processor programmed to execute an analyte correction forcorrecting a measurement of the sample due to one or more interferents,comprising: calculating an interferent impedance measurement including amagnitude measurement and a phase measurement using a switched capacitoraccumulator to measure a phase angle; and adjusting the measurement ofthe analyte in the sample using that the calculated interferentimpedance measurement.

In some aspects, the present disclosure provides a system for measuringa property of a sample, comprising a diagnostic measuring deviceconfigured to measure a concentration of an analyte in a sample; and thediagnostic measuring device further comprising a processor programmed toexecute an analyte correction for correcting a measurement of the sampledue to one or more interferents, comprising: calculating an interferentimpedance measurement including a magnitude measurement and a phasemeasurement using a switched capacitor accumulator to measure a phaseangle; and adjusting the measurement of the analyte in the sample usingthat the calculated interferent impedance measurement.

In some aspects, the present disclosure provides a method of measuring aproperty of a sample comprising: measuring an analyte in a sample;performing an analyte correction of the measured analyte due to one ormore interferents, comprising: calculating an interferent impedancemeasurement including a magnitude measurement and a phase measurementusing a switched capacitor accumulator to measure a phase angle; andadjusting the measurement of the analyte in the sample using that thecalculated interferent impedance measurement.

In some embodiments, the at least one interferent is hematocrit. In someembodiments, the test strip comprises: a conductive pattern including atleast one electrode at the proximal region of the test strip, electricalstrip contacts disposed at a conductive region at the distal region ofthe test strip, and conductive traces electrically connecting theelectrodes to at least some of the electrical strip contacts; a reagentlayer contacting at least a portion of at least one electrode; and achamber at the proximal region of the test strip for receiving thesample. In some embodiments, measuring the phase angle comprisesaccumulating time differences that represent phase over a sample windowto generate a signal large enough to be measured to calculate the phasemeasurement. In some embodiments, the switched capacitor accumulator canmeasure the phase measurement at high frequencies. In some embodiments,the frequency can be up to 500 kHz.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure is further described in the detailed descriptionwhich follows, in reference to the noted plurality of drawings by way ofnon-limiting examples of exemplary embodiments, in which like referencenumerals represent similar parts throughout the several views of thedrawings, and wherein:

FIG. 1A is a general cross-sectional view of a test strip according tosome embodiments of the present disclosure;

FIG. 1B is a top view of a conductive pattern on a substrate of a teststrip according to some embodiments of the present disclosure;

FIGS. 2A and 2B illustrate a meter according to some embodiments of thepresent disclosure;

FIG. 3 illustrates an exemplary embodiment of a voltage peak detector;

FIG. 4 illustrates an exemplary embodiment of a current peak detector;

FIG. 5 is an exemplary excitation signal chain circuit diagram;

FIG. 6 is an exemplary circuit for level shifting a digital signal;

FIG. 7 is an exemplary circuit for magnitude measurement;

FIG. 8 is an exemplary switch capacitor accumulator;

FIG. 9 is an exemplary graph showing phase as a function of terminalvoltage from the switched capacitor accumulator circuit; and

FIG. 10 is an exemplary flow chart showing an algorithm for correctingglucose measurements.

While the above-identified drawings set forth presently disclosedembodiments, other embodiments are also contemplated, as noted in thediscussion. This disclosure presents illustrative embodiments by way ofrepresentation and not limitation. Numerous other modifications andembodiments can be devised by those skilled in the art which fall withinthe scope and spirit of the principles of the presently disclosedembodiments.

DETAILED DESCRIPTION

In order to determine a measurement of an analyte, such as bloodglucose, in a sample, such as blood, using a device, such as a bloodglucose meter, certain interferents can be accounted for to increase theaccuracy of the measurement. For example, one such interferent is thehematocrit (HCT) concentration in the blood. In some embodiments, amethod of measuring the HCT for a blood glucose meter using the currentresponse to a step voltage excitation input, including peak current, anddecay rate can be mapped to various HCT levels.

The following description provides exemplary embodiments only, and isnot intended to limit the scope, applicability, or configuration of thedisclosure. Rather, the following description of the exemplaryembodiments will provide those skilled in the art with an enablingdescription for implementing one or more exemplary embodiments. It willbe understood that various changes may be made in the function andarrangement of elements without departing from the spirit and scope ofthe presently disclosed embodiments

Specific details are given in the following description to provide athorough understanding of the embodiments. However, it will beunderstood by one of ordinary skill in the art that the embodiments maybe practiced without these specific details. For example, systems,processes, and other elements in the presently disclosed embodiments maybe shown as components in block diagram form in order not to obscure theembodiments in unnecessary detail. In other instances, well-knownprocesses, structures, and techniques may be shown without unnecessarydetail to avoid obscuring the embodiments.

Also, it is noted that individual embodiments may be described as aprocess which is depicted as a flowchart, a flow diagram, a data flowdiagram, a structure diagram, or a block diagram. Although a flowchartmay describe the operations as a sequential process, many of theoperations can be performed in parallel or concurrently. In addition,the order of the operations may be re-arranged. A process may beterminated when its operations are completed, but could have additionalsteps not discussed or included in a figure. Furthermore, not alloperations in any particularly described process may occur in allembodiments. A process may correspond to a method, a function, aprocedure, a subroutine, a subprogram, etc. When a process correspondsto a function, its termination corresponds to a return of the functionto the calling function or the main function.

Subject matter will now be described more fully with reference to theaccompanying drawings, which form a part hereof, and which show, by wayof illustration, specific example aspects and embodiments of the presentdisclosure. Subject matter may, however, be embodied in a variety ofdifferent forms and, therefore, covered or claimed subject matter isintended to be construed as not being limited to any example embodimentsset forth herein; example embodiments are provided merely to beillustrative. The following detailed description is, therefore, notintended to be taken in a limiting sense.

A Blood Glucose Meter (BGM) is a portable, handheld device used tomeasure blood glucose levels for users with Type I or Type II diabetes.A Hemoglobin (HbG) meter measure blood hematocrit to compute Hemoglobin.

Typically, the user purchases tiny strips that interface with the BGM.The user draws a tiny amount of blood (a few microliters or less) from afinger or other area using a lancer. They then insert the strip into theBGM connector port. Now they apply the blood droplet onto the exposedend of the strip which has an open port for the blood. A chemicalreaction occurs between the blood sample and the chemistry on the strip,which is measured by the BGM to determine the blood glucose level inunits of mg/dL or mmol/L, depending on regional preferences andhematocrit as a percentage. Alternately, continuous blood glucose metersmeasure blood that is continuously provided via a patch. Hemoglobin ismeasured in g/dL.

The BGM measures blood glucose by analyzing the electrical response toan excitation signal. However, this response is dependent on thehematocrit (HCT) concentration in the blood. The accuracy of the glucosemeasurement is therefore dependent on the accuracy of the HCTconcentration to compensate the measurement for this interferent.

The present disclosure provides systems and methods for hematocritmeasurement. In particular, the present disclosure provides systems andmethods for obtaining a hematocrit impedance measurement for a bloodglucose meter. In some embodiments, a low cost low power microcontrollercan be used to measure complex impedance. No high sampling rates areneeded for high frequency signals for magnitude and phase measurements.In some embodiments, a phase measurement using the switched capacitoraccumulator method can take fast, narrow time pulse measurements andaccumulate them over a sample window so the phase can be measuredaccurately without high precision instrumentation. The presentdisclosure provides a switched capacitor accumulator method to measurenarrow pulse phase at high frequencies (up to 500 kHz). In someembodiments, peak detector circuits can be used to allow easymeasurement of impedance magnitude with low cost, low powermicrocontroller suitable for handheld devices.

A meter for measuring blood glucose or another analyst can include aportable, handheld device used to measure blood glucose levels for userswith Type I or Type II diabetes. Typically, the user purchases teststrips that interface with the meter. The user draws a tiny amount ofblood (a few microliters or less) from a finger or other area using alancer and a blood droplet is applied onto the exposed end of the stripwhich has an open port for the blood. The strip is inserted into themeter connector port and a chemical reaction occurs between the bloodsample and the chemistry on the strip, which is measured by the meter todetermine the blood glucose level in units of mg/dL or mmol/L, dependingon regional preferences.

FIG. 1A illustrates a general cross-sectional view of an exampleembodiment of a test strip 10. In particular, FIG. 1A depicts a teststrip 10 that includes a proximal end 12, a distal end 14, and is formedwith a base layer 16 extending along the entire length of test strip 10.The base layer 16 is preferably composed of an electrically insulatingmaterial and has a thickness sufficient to provide structural support totest strip 10. For purposes of this disclosure, “distal” refers to theportion of a test strip further from the fluid source (e.g., closer tothe meter) during normal use, and “proximal” refers to the portioncloser to the fluid source (e.g., a fingertip with a drop of blood for aglucose test strip) during normal use. The base layer 16 may be composedof an electrically insulating material and has a thickness sufficient toprovide structural support to test strip 10.

As seen in FIG. 1A, the proximal end 12 of test strip 10 includes asample receiving location, such as a sample chamber 20 configured toreceive a patient's fluid sample, as described above. The sample chamber20 may be formed in part through a slot in a dielectric insulating layer18 formed between a cover 22 and the underlying measuring electrodesformed on the base layer 16. Accordingly, the sample chamber 20 mayinclude a first opening, e.g., a sample receiving location, in theproximal end of the test strip and a second opening for venting thesample chamber 20. The sample chamber 20 may be dimensioned to be ableto draw the blood sample in through the first opening, and to hold theblood sample in the sample chamber 20, by capillary action. The teststrip 10 can include a tapered section that is narrowest at the proximalend 12, or can include other indicia to make it easier for the user tolocate the first opening and apply the blood sample.

In reference to FIG. 1B, in accordance with an example embodiment of thepresent disclosure, the strip 10 can include a conductive patterndisposed on base layer 16 of the strip 10. In some embodiments, theconductive pattern may be formed by laser ablating the electricallyinsulating material of the base layer 16 to expose the electricallyconductive material underneath. Other methods may also be used, such asinserted conductors with physical attachment to control circuit. Othermethods may also be used to dispose the conductive pattern on the baselayer. The conductive pattern may include a plurality of electrodes 15disposed on base layer 16 near proximal end 12, a plurality ofelectrical strip contacts 19 disposed on base layer 16 near distal end14, and a plurality of conductive traces 17 electrically connecting theelectrodes 15 to the plurality of electrical strip contacts 19.

In some embodiments, a reagent layer may be disposed on the base layer16 of the strip 10 in contact with at least a working electrode of theconductive pattern. The reagent layer may include an enzyme, such asglucose oxidase, and a mediator, such as potassium ferricyanide orruthenium hexamine. Reagent layer 90 may also include other components,such as buffering materials (e.g., potassium phosphate), polymericbinders (e.g., hydroxypropyl-methyl-cellulose, sodium alginate,microcrystalline cellulose, polyethylene oxide, hydroxyethylcellulose,and/or polyvinyl alcohol), and surfactants (e.g., Triton X-100 orSurfynol 485). With these chemical constituents, the reagent layerreacts with glucose in the blood sample in the following way. Theglucose oxidase initiates a reaction that oxidizes the glucose togluconic acid and reduces the ferricyanide to ferrocyanide. When anappropriate voltage is applied to working electrode, relative to counterelectrode, the ferrocyanide is oxidized to ferricyanide, therebygenerating a current that is related to the glucose concentration in theblood sample. As would be appreciated by one skilled in the art, anycombination of strips 10 known in the art can be utilized withoutdeparting from the scope of the present disclosure.

FIG. 2A and FIG. 2B illustrate, an exemplary illustration of a meter 100used to measure the glucose level in a blood sample. The meter 100includes a housing having a test port for receiving the test strip, anda processor or microprocessor programmed to perform methods andalgorithms to determine glucose concentration in a test sample orcontrol solution as disclosed in the present disclosure. in someembodiments, the meter 100 has a size and shape to allow it to beconveniently held in a user's hand while the user is performing theglucose measurement. The meter 100 may include a front side 102, a backside 104, a left side 106, a right side 108, a top side 110, and abottom side 112. The front side 102 may include a display 114. such as aliquid crystal display (LCD). A bottom side 112 may include a shipconnector 116 into which test strip can be inserted to conduct ameasurement. The meter 100 may also include a storage device for storingtest algorithms or test data. The left side 106 of the meter 100 mayinclude a data connector 418 into which a removable data storage device120 may be inserted, as necessary. The top side 110 may include one ormore user controls 122, such as buttons, with which the user may controlmeter 100, and the right side 108 may include a serial connector (notshown).

In some embodiments, the blood glucose meter comprises a decoder fordecoding a predetermined electrical property, e.g. resistance, from thetest strips as information. The decoder operates with, or is a part of,the microprocessor.

The meter can be programmed to wait for a predetermined period of timeafter initially detecting the blood sample, to allow the blood sample toreact with the reagent layer or can immediately begin taking readings insequence. During a fluid measurement period, the meter applies an assayvoltage between the working and counter electrodes and takes one or moremeasurements of the resulting current flowing between the working andcounter electrodes. The assay voltage is near the redox potential of thechemistry in the reagent layer, and the resulting current is related tothe concentration of the particular constituent measured, such as. forexample, the glucose level in a blood sample.

In one example, the reagent layer may react with glucose in the bloodsample to determine the particular glucose concentration. In oneexample, glucose oxidase is used in the reagent layer. The recitation ofglucose oxidase is intended as an example only and other materials canbe used without departing from the scope of the present disclosure.Other possible mediators include, but are not limited to, ruthenium andosmium. During a sample test, the glucose oxidase initiates a reactionthat oxidizes the glucose to gluconic acid and reduces the ferricyanideto ferrocyanide. When an appropriate voltage is applied to a workingelectrode, relative to a counter electrode, the ferrocyanide is oxidizedto ferricyanide, thereby generating a current that is related to theglucose concentration in the blood sample. The meter then calculates theglucose level based on the measured current and on calibration data thatthe meter has been signaled to access by the code data read from thesecond plurality of electrical contacts associated with the test strip.The meter then displays the calculated glucose level to the user.

A correction based on a measured HCT value can be applied to glucoselevel determined by the meter. In some embodiments, the HCT measurementsequence begins after a drop of blood or control is detected when thedrop completes the circuit between the HCT measurement anode andcathode. In some embodiment, the HCT is analyzed based on an electricalmeasurement between two electrodes on the test strip separate from theelectrodes used to measure glucose, or the electrodes can be shared forboth measurements. After the drop is detected and either before, during,or after glucose measurement in the case of a glucose meter, anexcitation voltage signal is applied to the HCT electrodes. The saltcontent of blood creates an electronic signature, in which the magnitudeand phase response can be mapped to the HCT of the blood. The impedanceof the electrical signature is affected by temperature, so the true HCTreading is corrected for temperature for the temperature difference from24° C. (dT).

In some embodiments, the glucose measurement sequence is initiated onlywhen the meter detects a full sample chamber. The glucose in the testsample is oxidized by the enzyme glucose dehydrogenase-FAD, producinggluconolactone and the reduced form of an electron mediator. The reducedmediator is then oxidized at the surface of the glucose measurementanode to produce an electrical signal (current in nanoamp units) that isdetected by the meter. The electrical signal (current, in nanoamps)produced by oxidation of the reduced mediator at the surface of theglucose measurement anode is proportional to the amount of glucose inthe test sample. The HCT value (which can be temperature corrected) isthen used to determine the temperature corrected glucose value.

The meter can measure blood glucose by analysing the electrical responseto an excitation signal. However, this response is dependent on the HCTconcentration in the blood. The accuracy of the glucose measurement istherefore dependent on the accuracy of the HCT concentration tocompensate the measurement for this interferent. For a given bloodglucose sample, the peak response current to a voltage excitation usedto measure blood glucose on the blood sample can be inverselyproportional to the HCT concentration in the blood. Knowing the HCTimpedance provides the data to map the HCT concentration to the peakcurrent through empirical methods. This known HCT concentration (% HCT)can then be used to adjust blood glucose measurement. Hemoglobinconcentration is converted directly from percent HCT.

Various systems and methods can be used for measuring the HCTconcentration from step response to impedance measurement. In someembodiments, a method of measuring the HCT for a blood glucose meterincludes using multiple setpoints of relatively high frequency (10kHz-500 kHz) magnitude and phase measurements to measure the HCTimpedance. In some embodiments, the phase measurement is done usingnarrow time pulse measurements that can be accumulated over a samplewindow.

In some embodiments, a method of measuring the HCT for a blood glucosemeter can mix analog and digital circuitry to measure the HCT compleximpedance (HCT impedance magnitude and phase).

One limitation of many microcontrollers suitable for handheld meters isthat they have limited sampling rates making accurate magnitude andtiming resolution for phase difficult. In some embodiments, bothmagnitude and phase signals are offloaded to separate analog circuitryfor processing and converted to a simple DC output measurement suitablefor most microcontrollers.

Additionally, in some embodiments, measurements can be taken at aplurality of frequencies. In some embodiments, frequencies in the rangeof 10 kHz to 500 kHz can be used. For example, measurements can be takenat up to three different frequencies (e.g. 20 kHz, 71 kHz, 200 kHz). Aunique method can be provided for generating up to 3 frequencies, butmore can be easily extended. To generate the frequencies, as describedin FIG. 5, a squarewave can be generated by a microcontroller at thefrequency of interest and is then multiplexed to the matching analog lowpass filter circuit to generate a pure sine wave excitation at thisfrequency. The microcontroller can generate these digital frequenciesand the analog circuitry can have a multiplexer input/output for eachunique frequency desired as well as a low pass filter for each uniquefrequency desired. For example, FIG. 5 shows three unique frequencieswith three multiplexer outputs and three low pass filters. Furthermore,in some embodiments DC bias is not desirable when exciting the bloodsample, and too high an excitation amplitude can damage the sample.Therefore, the maximum signal amplitude can be very low (<100 mV), be inthe form of a pure sine wave, and have 0 DC bias.

Magnitude

The magnitude of the impedance is a measure of V(ω)/I(ω). This presentsa challenge to most microcontrollers as the frequency of excitation canbecome high, for example, a range of 10 kHz-500 Khz. The solution liesin accurately detecting the peak of V(ω) and the peak of I(ω) andcomputing the magnitude as

|Z(ω)|=Vpk(ω)/Ipk(ω)

FIG. 3 illustrates an exemplary embodiment of a V(ω) peak detector usinga comparator for high frequencies measurement of peak voltage. When anAC voltage is applied to the non-inverting input of the comparator(+input), if the voltage on the capacitor is less than the peak inputvoltage, then the comparator output will go “open collector” and chargethe capacitor through R_(PU), until capacitor C is charged to the peakvoltage at a DC level. Each AC cycle the capacitor discharges a littlebut is refreshed by the comparator each cycle to keep a stable DCvoltage on the capacitor which is read by the microcontroller on andanalog to digital (ADC) channel. Once the measurement is complete, themicrocontroller will switch the ADC input function to GPIO output LO todischarge the capacitor to start a fresh measurement without residualvoltage from the last measurement. The output Vpk(ω) is the demodulatedDC output input to an ADC through R_(CLR), which is chosen to be a smallresistance, such as 100 Ω, as needed for an accurate measurement by anADC. This input to the ADC can then be switched to a digital output,active LO to clear the output for the next measurement.

At high frequencies, for example up to 500 kHz, most peak detectionusing op amps will not accurately measure the peak. In some embodiments,a comparator is used to accurately measure peaks at high frequencies.FIG. 4 illustrates an exemplary embodiment of a I(ω) peak detector usinga comparator for high frequencies measurement of peak current. I(ω) isan AC sinusoidal voltage signal that is proportional to current. Thecircuit in FIG. 4 functions the same as the circuit in FIG. 3 except thevoltage input/output is a scaled representation of the current.

Various comparators can be used to measure peak voltage and/or peakcurrent. In some embodiments, rail to rail input and output comparatorscan be used. Furthermore, the power supplies can be bipolar (±V) tosupport the sinusoidal AC input signal which swings between negativemaximums, through zero (zero bias), to positive maximums. A pullupresistor of (1kΩ-4.99kΩ) can provide a quick charge of capacitor C eachsinusoidal cycle. When the measurement is done, the signal can becleared by switching the ADC input of Ipk(ω) to a GPIO output and clearthe peak voltage Vpk(ω) before the next measurement by driving theoutput LO. R_(CLR) should be in the range of a few hundred ohms todischarge the capacitor quickly.

Excitation Signal Chain

As shown in FIG. 5, the microcontroller generates a square wave digitalexcitation at the desired frequency (up to 500 kHz). This is easilyaccomplished on most low cost low power microcontrollers capable ofoperating at bus speeds of 8 MHz or greater. This signal is a digital0-3V level and can be processed into a pure sine wave at <100 mVamplitude and 0 DC bias. For example, an acceptable output signal wouldbe ±90 mV sine wave, centered around ground (0V). This level shiftingresults in a low level square wave signal going positive and negativecentered around zero volts. This low level signal is buffered to provideimpedance matching before being sent to the multiplexer where one ofthree low pass filters will convert the low level square wave signalinto a low level sinusoidal signal by filtering out all frequencies forthe square wave except the fundamental. The output of the selected lowpass filter is then multiplexed to the next stage where any resultant DCerror offset is removed with a DC block circuit, usually just a passiveRC high pass filter. Finally, the low level AC signal is buffered forimpedance matching and output to the anode electrode. FIG. 5 illustratesan exemplary V(ω) excitation signal chain block diagram.

Therefore, the digital excitation is level shifted to ±(<100 mV) andbuffered. This level shifting can be accomplished using a combination ofcomparator and Schottky diodes, as shown in FIG. 6. FIG. 6 Illustrates acircuit for level shifting a digital signal to ±(V_(D)) using oneschottky diode drop of ˜400 mV. V(ω) is scaled down by R1/R2 and iscomparted to the DC reference voltage generated by R3/R4 voltage dividerfrom V_(CC) supply voltage. This generates an AC output voltage thatswings from +V_(CC) to −V_(EE) supplying the comparator (example±2.75V). RHYS provides hysteresis so there is no gitter on transitionsaround the reference voltage switchover point. The comparator outputswings from open collector to negative supply, as V(ω) swings frompositive to negative each AC cycle. On the open collector cycle, D1 isforward biased and conducts resulting in an output voltage one diodedrop +V_(D). On the negative cycle, the output of the comparator is−V_(EE) (example −2.75V) and D2 conducts resulting in an output voltageof one diode drop −V_(D), typically ±400 mV AC signal is generated bythis circuit. R_(PU) is needed because the comparator is typically anopen collector type which uses the energy of V_(CC) to provide a HIlevel output R_(L) can limit the current through D₁/D₂.

The next step is to select the proper low pass analog filter to pass thesignal through. Once this step is taken, the signal will be a pure sinewave (<±100 mV) amplitude, as the filtering process reduces the signalamplitude as higher frequency harmonics are attenuated. A frequency ischosen by the microcontroller using two digital control lines FSEL1 andFSEL0.

The low pass filters can be any combination of active or passive lowpass filters to achieve a 4^(th) order attenuation at the chosenfrequency. In some embodiments, low pass filters that can be usedinclude but are not limited to a Sallen-key filter and a Bessel filter.

Finally, the sine wave chosen is sent to a DC block circuit before beingbuffered to excite the anode electrode.

The cathode current is measured with a transimpedance amplifier (TIA)which generates a current propostional to voltage, in this case at thefrequency of excitation. Both the excitaiton signal and current responsesignal are amplified through gain stages and the peaks extracted. Thesepeaks are DC measurements read by the microcontroller's analog todigital converter (ADC) channels (FIG. 7). FIG. 7 shows two electrodes(anode and cathode). The anode, excited by voltage excitation V(ω) goesto a gain stage with peak detected to be measured by the microcontrollerADC. The cathode, where current flow from the blood sample into the TIAto generate an AC voltage proportional to the AC current, then goes to again stage with peak detected to be measured by the microcontroller ADC.

The impedance magnitude is calculated as the ratio:

|Z|=Peak V/Peak I

Phase Measurement

The phase measurement is an important part of the complex impedance.Magnitude by itself does not provide for the reactance component Xc.

The problem with the phase measurement is that at high frequencies thetime difference that the phase represents is too small to measure withmicrocontrollers suitable for handheld devices. For example, 1° phase at220 kHz is equal to only 12.6 ns, which would be too small to accuratelymeasure with timer capture channels on low cost low powermicrocontrollers suitable for handheld devices.

In some embodiments, measuring the phase angle is accomplished byaccumulating these small time differences over a sample window toprovide a larger signal to measure representing the phase.

Switched Capacitor Accumulator

An exemplary embodiment of a switched capacitor accumulator for narrowpulse phase measurement is shown in FIG. 8. Narrow phase pulses can begenerated by a phase detector. This can be any well known technique suchas XOR, flip flop, etc. These narrow pulses enable a SPST analog switchwhich connects a reference voltage to the charge circuit. A second SPSTanalog switch in series with the first acts as a sample and hold. Duringa known sample window, the reference voltage will charge the RC circuitto ramp up a voltage proportional to the phase angle.

Once the sample window is done, the value is held by the sample and hold(S/H switch open) so the microcontroller can read the DC voltage.Finally, after the signal is read, the voltage on the capacitor isdischarged by changing the ADC input phase to a GPIO output LO to clearthe signal for the next measurement.

An exemplary graph depicting a transfer function of the switch capacitoraccumulator is shown in FIG. 9. In an exemplary embodiment, resistanceR=4.99 kΩ, and capacitance C=0.47 uF.

The transfer function is an RC charge over a sample window. A derivationshows that the phase is proportional to Vph from this circuit in thefollowing nonlinear equation:

∅ = - RC   ln  ( 1 - V R )  360 ° 2  T w

In some embodiments, the transfer function is independent of frequency.The phase only depends on the value of the resistance, capacitance,reference voltage (typically 1 to 1.5V) and the sample window T_(W) andthe value of Vph. Of these, only Vph is a variable, all others are knownconstants.

For example, for a sample window of 10 ms, the transfer function isdependent only on

Vph as the other parameters are all constants.

∅ = - RC   ln  ( 1 - V R )  18 , 000 °

Different values of resistance and capacitance can be chosen dependingon the range of phase of interest. For example, a larger time constant(RC), where R=4.99 kΩ and C=0.47 uF gives a larger range of phase(0°-90°) whereas a smaller time constant where R=2.2 kΩ and C=0.47 uFbetter for phases (0°-30°).

Once the phase is known, then together with the impedance magnitude, thereactance Xc can be calculated as:

Xc=|Z|*sin(Ø)

Laboratory measurements map Xc to percent HCT concentrations. Knownglucose concentrations are measured with different HCT percentages tomap the interference. These adjustments are implemented into the glucosealgorithms to compensate for the HCT interference. For example, at thesame glucose levels, the impedance is higher at higher HCT. This can becompensated.

In some embodiments, the systems of the present disclosure may be usedto measure glucose concentration in blood, among other measurements, asdiscussed above. Once the meter has performed an initial check routine,the meter can apply a drop-detect voltage between working and counterelectrodes and detect a fluid sample, for example, a blood sample, bydetecting a current flow between the working and counter electrodes(i.e., a current flow through the blood sample as it bridges the workingand counter electrodes). For example, in some embodiments, the meter maymeasure an amount of components in blood which may impact the glucosemeasurement, such as, for example, a level of hematocrit or of aninterferant. The meter can later use such information to adjust theglucose concentration to account for the hematocrit level and thepresence of the interferants in blood, among other things. Thesemeasurements can also be corrected based on the temperature. The metercan then adjust the glucose level, as necessary, based on themeasurements of the temperature, hematocrit and the presence ofinterferants. Non-limiting examples of algorithms for glucose levelcorrection are presented in FIG. 10. Errors can be displayed ifencountered.

FIG. 10 is an embodiment flow chart for correcting the analyte value1200, wherein the analyte specific current is modified based ontemperature and hematocrit and interference currents to then generate acorrected analyte value. For example, equations may be IC=IA−S×II, whereIC is the corrected current, IA is the current measured from the analyteanode, II is the current measured from the interference anode, and S isan empirically derived scaling factor. The present calculation mayeliminate the need to make complicated calculation and/or voltageapplication schemes. The present calculation uses a mathematicallymodified (scaled) subtraction of the interference current from thecurrent from the analyte specific anode. The interference current may bemultiplied by an empirically determined constant that is dependent onlyon the relative areas of the two electrodes, not on the relative effectsof hematocrit and temperature variations on the two currents. This isbecause the two reagents (analyte and interference) are formulated torespond the same way to hematocrit and temperature variations. Thus,referring to FIG. 10, the raw glucose signal 1201 would be correctedwith the raw interference signal 1202 to obtain an interferencecorrected glucose signal 1203, where a temperature correction isincorporated to obtain an interference and temperature corrected glucosevalue 1204. The raw HCT signal 1205 is corrected to obtain a temperaturecorrected HCT 1206. The interference & temperature corrected glucosevalue 1204 may then be incorporated with the temperature corrected HCT1206 to obtain an interference, temperature & HCT corrected glucosevalue 1207.

It is also possible to first make temperature and hematocrit adjustmentsto the interference current and then subtract it from the raw analytecurrent and then subject that corrected current to another temperatureand hematocrit adjustment. In some embodiments, it may be possible tocorrect the analyte and interference currents separately for temperatureand hematocrit, and then convert each separately to an uncorrectedglucose value and to a glucose equivalent value, respectively. Then theglucose equivalent value can be subtracted from the uncorrected glucosevalue to obtain a corrected glucose value.

In some embodiments, it is possible to use the present calculation toalso first convert the interference current to analyte equivalents andthen subtract it from the amount of analyte of interference and subtractthat number. That is, the correction can occur before or aftermathematically processing the current. For example, by having theinterference anode larger for improved signal to noise ratio due to thecurrents being so small, at least one aspect includes using a scalingfactor and anodes of different surface area.

It should be noted that while the operation of the system of the presentdisclosure has been described primarily in connection with determininghematocrit concentration in blood to ultimately compute glucoseconcentration in blood, the systems of the present disclosure may beconfigured to measure other analytes in blood as well as in otherfluids, as discussed above.

Numerous modifications and alternative embodiments of the presentdisclosure will be apparent to those skilled in the art in view of theforegoing description. Accordingly, this description is to be construedas illustrative only and is for the purpose of teaching those skilled inthe art the best mode for carrying out the present disclosure. Detailsof the structure may vary substantially without departing from thespirit of the present disclosure, and exclusive use of all modificationsthat come within the scope of the appended claims is reserved. Withinthis specification embodiments have been described in a way whichenables a clear and concise specification to be written, but it isintended and will be appreciated that embodiments may be variouslycombined or separated without parting from the disclosure. It isintended that the present disclosure be limited only to the extentrequired by the appended claims and the applicable rules of law.

It is also to be understood that the following claims are to cover allgeneric and specific features of the disclosure described herein, andall statements of the scope of the disclosure which, as a matter oflanguage, might be said to fall therebetween.

What is claimed is:
 1. A system for measuring a property of a sample,comprising: a test strip for collecting the sample; a diagnosticmeasuring device configured to receive the test strip and measure aconcentration of an analyte in the sample received on the test strip;and the diagnostic measuring device further comprising a processorprogrammed to execute an analyte correction for correcting a measurementof the sample due to one or more interferents, comprising: calculatingan interferent impedance measurement including a magnitude measurementand a phase measurement using a switched capacitor accumulator tomeasure a phase angle; and adjusting the measurement of the analyte inthe sample using that the calculated interferent impedance measurement.2. The system of claim 1, wherein the analyte is glucose and the atleast one interferent is hematocrit.
 3. The system of claim 1, whereinthe test strip comprises: a conductive pattern including at least oneelectrode at the proximal region of the test strip, electrical stripcontacts disposed at a conductive region at the distal region of thetest strip, and conductive traces electrically connecting the electrodesto at least some of the electrical strip contacts; a reagent layercontacting at least a portion of at least one electrode; and a chamberat the proximal region of the test strip for receiving the sample. 4.The system of claim 1, wherein measuring the phase angle comprisesaccumulating time differences that represent phase over a sample windowto generate a signal large enough to be measured to calculate the phasemeasurement.
 5. The system of claim 1, wherein the switched capacitoraccumulator can measure the phase measurement at high frequencies. 6.The system of claim 5, wherein the frequency can be up to 500 kHz.
 7. Asystem for measuring a property of a sample, comprising: a diagnosticmeasuring device configured to measure a concentration of an analyte ina sample; and the diagnostic measuring device further comprising aprocessor programmed to execute an analyte correction for correcting ameasurement of the sample due to one or more interferents, comprising:calculating an interferent impedance measurement including a magnitudemeasurement and a phase measurement using a switched capacitoraccumulator to measure a phase angle; and adjusting the measurement ofthe analyte in the sample using that the calculated interferentimpedance measurement.
 8. The system of claim 7, the analyte is glucoseand the at least one interferent is hematocrit.
 9. The system of claim7, wherein measuring the phase angle comprises accumulating timedifferences that represent phase over a sample window to generate asignal large enough to be measured to calculate the phase measurement.10. The system of claim 7, wherein the switched capacitor accumulatorcan measure the phase measurement at high frequencies.
 11. The system ofclaim 10, wherein the frequency can be up to 500 kHz.
 12. A method ofmeasuring a property of a sample comprising: measuring an analyte in asample; performing an analyte correction of the measured analyte due toone or more interferents, comprising: calculating an interferentimpedance measurement including a magnitude measurement and a phasemeasurement using a switched capacitor accumulator to measure a phaseangle; and adjusting the measurement of the analyte in the sample usingthat the calculated interferent impedance measurement.
 13. The method ofclaim 12, wherein the analyte is glucose and the at least oneinterferent is hematocrit.
 14. The method of claim 12, furthercomprising applying a temperature correction to the interferentimpedance measurement.
 15. The method of claim 12, wherein measuring thephase angle comprises accumulating time differences that represent phaseover a sample window to generate a signal large enough to be measured tocalculate the phase measurement
 16. The method of claim 12, wherein theswitched capacitor accumulator can measure the phase measurement at highfrequencies.
 17. The method of claim 16, wherein the frequency can be upto 500 kHz.